Clinical trials on drugs for cancer with various conditionally replicating (genetically engineered to replicate specifically in a cancer cell) viruses have been previously reported (Non Patent Literature 1). Although treatments of cancer with these drugs have achieved certain results, the effect is limited in most cases, and development of more effective drugs is desired.
Representative examples of drugs for cancer with a conditionally replicating virus for which results of a clinical trial have been reported include Telomelysin (Non Patent Literature 2), which contains an adenovirus type 5 as a skeleton, and Talimogene laherparepvec (T-VEC, old name: Oncovex) (Non Patent Literature 3), which contains a herpes simplex virus type 1 as a skeleton.
In recent years, it has been considered important to allow drugs for cancer with a virus to have a function of activating anticancer immunity. From this viewpoint, although Telomelysin (Non Patent Literature 2) can induce cancer cell death through replication of the adenovirus at a location of administration, it does not encode a cytokine gene or the like which activates anticancer immunity, and thus a strong, systemic anticancer immunity-activating effect is not expected. This may limit the therapeutic effect of Telomelysin.
T-VEC is expected to provide cancer cell death and impart antigenicity to a cancer cell through replication of the herpes virus at a location of administration and to activate anticancer immunity through expression of the cytokine GM-CSF. Although the cytokine GM-CSF has an anticancer immunity-activating effect to induce a dendritic cell as a cancer antigen-presenting cell, to differentiate (Non Patent Literature 1), it has been also reported that the cytokine GM-CSF in a high dosage may induce an immunosuppressive cell to reduce the anticancer immune function to worsen disease condition (Non Patent Literature 4), which may limit the therapeutic effect of T-VEC.
Thus, development of more effective drugs for cancer is desired in light of the above problems of existing drugs for cancer with a conditionally replicating virus. As a conditionally replicating adenovirus to solve the above problems, conditionally replicating adenoviruses having various mutations have been reported (Patent Literatures 1 and 2 and Non Patent Literatures 5 to 10).
On the other hand, an REIC (REIC/Dkk-3) gene is known as a gene associated with immortalization of a cell, and it has been reported that expression of this gene is suppressed in cancer cells, and that the REIC gene is used for treatment of cancers (Patent Literature 3). The REIC has an anticancer immunity-activating effect and an effect of inducing cancer cell death through endoplasmic reticulum stress in gene expression. It is further reported that a partial fragment of the REIC gene has the same effect as the full length REIC (Patent Literature 4), and furthermore an adenovirus to express the REIC/Dkk-3 gene has been reported (Patent Literature 5 and Non Patent Literature 11).